Tylosin A (2-((4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-(((2R,3R,4R,5S,6R)-5-(((2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-16-ethyl-4-hydroxy-15-((((2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)methyl)-5,9,13-trimethyl-2,10-dioxooxacyclohexadeca-11,13-dien-7-yl)acetaldehyde) is a macrolide antibiotic that is commonly used to treat veterinary infections. Tylosin A has a broad range of activity against Gram-positive organisms, with activity against a few Gram-negative species. Its high safety margin has led to its non-selective use as a food additive in meat production, and as a growth promoting agent. However, tylosin A and its derivatives have seen only limited use in companion animal health care. Tylvalosin, a derivative of tylosin, is available commercially as Aivlosin®. Aivlosin® is used for treating bacterial infections in farm animals. Neither tylosin A nor its derivatives are approved for use in human disease.
In part, the use of tylosin A and its analogs has been limited by their marginal pharmacokinetic profiles. Tylosin A has a relatively short half-life in vivo, and is poorly absorbed from an oral dose. The oral bioavailability of tylosin A in mammals is low. Thus, a tylosin A analog or derivative with improved pharmacokinetic properties would be a valuable addition to the treatment options for human and veterinary infections.
The mycarosyl group of Tylosin A can be cleaved to form desmycarosyl tylosin or tylosin B. Several groups have reported tylosin B analogs or derivatives with improved pharmacokinetic properties. Narandja et al. (J. Antibiotics 1995, 248) reported a derivative of tylosin B that gives tissue drug levels 2-3 times those of the parent. The commercial antibiotic tilmicosin (EL-870) is a semi-synthetic derivative of tylosin B and has been demonstrated to have a superior drug level profile when compared with the parent compound (Ose, E. E., J. Antibiotics 1987, 190). Tilmicosin is commercially available for prevention and treatment of bovine and ovine respiratory diseases associated with bacterial infection.
One particular challenge for the development of orally-bioavailable tylosin A derivatives is the susceptibility of tylosin esters (especially those derivatized at the 4″-position on the mycarose sugar) to hepatic esterases, as noted by Takeuchi et al. (J. Antibiotics 1987, 1358).